A new era in the treatment of chronic hepatitis C infection

Treatment of chronic hepatitis C virus (HCV) infection has evolved over the past three decades. At the start, treatment involved interferon monotherapy followed by combination therapy using interferon and ribavirin, and subsequently evolved to pegylated interferon (Peg-IFN) and ribavirin. In genotype 1 infection, rates of sustained virological response (SVR) are approximately 45 % with Peg-IFN and ribavirin, whereas SVR rates in genotypes 2 and 3 infections are as high as 70 % to 80 %. Side effects and cost related to these drugs are important concerns, particularly in countries like India where patients have to bear their health expenses. In the recent past, there has been a significant change in course with the on-going search and the development of more effective drugs in the management of HCV infection. Telaprevir and Boceprevir are two new potent protease inhibitors (direct acting antiviral or DAA agents) which, when administered with Peg-IFN and ribavirin, have shown to result significantly higher SVR rates in phase 3 studies in patients with genotype 1 infection, both in treatment naïve patients (up to 75 %) and those with previously failed therapy. Several other new antiviral agents some in combination with Peg-IFN and ribavirin and some in combination without Peg-IFN (IFN-free regimens) are currently being tested in patients with genotype 1, 2 and 3 infections and are expected to dramatically change the armamentarium of HCV therapy in the coming years.     

Expert opinion on boceprevir- and telaprevir-based triple therapies of chronic hepatitis C

With the approval of boceprevir and telaprevir the standard treatment of chronic hepatitis C virus (HCV) genotype 1 infection will be the triple therapy of a HCV protease inhibitor together with pegylated interferon alfa and ribavirin. In clinical studies a significant increase of sustained virological response rates from 38?-?44?% to 63?-?75?% for treatment-na?ve and from 17?-?21?% to 59?-?66?% in treatment-experienced patients in comparison to the dual combination therapy with pegylated interferon alfa and ribavirin alone has been demonstrated. In addition, a large number of treatment-na?ve patients and relapsers benefit from shorten treatment durations to 24?-?28 weeks. However, important differences exist between the administration of boceprevir and telaprevir in terms of a pegylated interferon alfa/ribavirin lead-in phase, the duration of dosing of the protease inhibitor, the overall treatment duration, HCV RNA measurements for response guided treatment durations and stopping rules. Furthermore, triple therapies with boceprevir and telaprevir may be associated with selection of resistant viral variants, new adverse events and clinically relevant drug-drug interactions. The present review gives an overview on the results of underlying clinical studies together with a guideline for the practical management of boceprevir- and telaprevir-based triple therapies.     

Hepatitis C: viral and host factors associated with non‐response to pegylated interferon plus ribavirin

Treatment for chronic hepatitis C virus (HCV) infection has evolved considerably in the last years. The standard of care (SOC) for HCV infection consists in the combination of pegylated interferon (PEG‐IFN) plus ribavirin. However, it only induces a sustained virological response (SVR) in half of genotype 1‐infected patients. Several viral and host factors have been associated with non‐response: steatosis, obesity, insulin resistance, age, male sex, ethnicity and genotypes. Many studies have demonstrated that in non‐responders, some interferon‐stimulated genes were upregulated before treatment. Those findings associated to clinical, biochemical and histological data may help detect responders before starting any treatment. This is a very important issue because the standard treatment is physically and economically demanding. The future of HCV treatment would probably consist in the addition of specifically targeted antiviral therapy for HCV such as protease and/or polymerase inhibitors to the SOC. In genotype 1 patients, very promising results have been reported when the protease inhibitor telaprevir or boceprevir is added to the SOC. It increases the SVR rates from approximately 50% (PEG‐IFN plus ribavirin) to 70% (for patients treated with a combination of PEG‐IFN plus ribavirin plus telaprevir). Different elements are associated with non‐response: (i) viral factors, (ii) host factors and (iii) molecular mechanisms induced by HCV proteins to inhibit the IFN signalling pathway. The goal of this review is to present the mechanisms of non‐response, to overcome it and to identify factors that can help to predict the response to anti‐HCV therapy.     

Effectiveness of triple therapy with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure

Favourable efficacy and safety profiles for simeprevir in combination with pegylated interferon alpha (PEG‐IFNα) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir‐based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir‐based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG‐IFNα and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment naïve [3/4 (75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG‐IFNα and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct‐acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG‐IFNα and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir‐based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG‐IFNα and ribavirin. For patients with prior null response to PEG‐IFNα and ribavirin, retreatment with simeprevir‐based triple therapy is not a useful option.     

Advances in the management of hepatitis C

Significant advances have recently been made in the management of hepatitis C virus (HCV) with many of the changes now part of routine clinical practice. These include the use of non‐invasive methods to assess liver fibrosis, interleukin 28B genotype testing to predict interferon responsiveness and the use of new anti‐viral regimens for HCV genotype 1. Two new antiviral agents (boceprevir and telaprevir) have recently become available in Australia. These protease inhibitors are used in combination with pegylated interferon and ribavirin as triple therapy for genotype 1 HCV. This combination increases sustained virological response from approximately 45–50% to 66–75% in treatment naïve patients. However, these new regimens present novel challenges including complicated treatment algorithms based on virological response, numerous drug interactions and additional side effects especially in patients with advanced fibrosis. The protease inhibitors are the first of many antiviral drugs to become available to treat HCV, heralding the arrival of new agents that will offer greater chances of cure with improved safety and tolerability compared with current therapies.     

Randomised, double blind, placebo controlled trial of interferon, ribavirin, and amantadine versus interferon, ribavirin, and placebo in treatment naïve patients with chronic hepatitis C

BACKGROUND AND AIM: In this study, we compared the efficacy of triple therapy (interferon alfa, ribavirin, and amantadine) with standard therapy (interferon alfa and ribavirin) in treatment na?ve patients with chronic hepatitis C virus (HCV). METHODS: In this prospective, randomised, double blind, placebo controlled, multicentre study, 85 patients (amantadine group) received a three drug regimen of interferon alfa-2b 3 million units three times per week, ribavirin 1000-1200 mg daily in divided doses, and amantadine 100 mg twice daily, and 86 patients (placebo group) received interferon alfa-2b, ribavirin, and identical placebo. Treatment was discontinued at 24 weeks if patients had detectable HCV RNA by polymerase chain reaction (PCR). All patients were followed for 24 weeks after completion of treatment. The primary end point was undetectable HCV-RNA by PCR at 24 weeks (sustained viral clearance) after completion of treatment. RESULTS: At the end of treatment, HCV RNA clearance was seen in 32.9% of the amantadine group and 38.4% of the placebo group (p=0.3). Sustained virological response was seen in 24.7% of the amantadine group and in 27.9% of the placebo group by intention to treat analysis; response rate was 30.4% and 34.8%, respectively, in those who completed 24 weeks of treatment. Poor response was seen in both groups among cirrhotics, African-Americans, genotype 1, and those with a higher viral load. By multivariate analysis, genotype 1, high viral load, and low serum albumin were the only predictors of poor response. Addition of amantadine to the standard regimen did not result in any unexpected side effects. CONCLUSION: Response to triple therapy of interferon alfa, ribavirin, and amantadine was similar to standard therapy of interferon alfa and ribavirin. Our results suggest that amantadine has no role in the management of HCV.     

Treatment of chronic hepatitis C with PEGylated interferon and ribavirin

Treatment with interferon alfa combined with ribavirin is successful in approximately 40% to 45% of patients with chronic hepatitis C viral infection (HCV). However, response rates are disappointing in patients who are difficult to treat, such as those infected with HCV genotype 1, high viral load, or advanced liver fibrosis. In addition, low tolerability and significant side effects of therapy frequently lead to dose reduction and treatment discontinuation, decreasing response rates further. Thus, investigation of new treatment options and innovations for chronic HCV infection are vital. This review describes recent advances in the treatment of HCV infection with PEGylated interferon (interferon modified with polyethylene glycol [PEG]) combined with ribavirin.     

Antiviral therapy for hepatitis C virus–associated mixed cryoglobulinemia vasculitis: A long‐term followup study

Objective

To evaluate the long‐term efficacy of anti–hepatitis C virus (HCV) therapy in patients with HCV‐associated mixed cryoglobulinemia (HCV‐MC) vasculitis and to assess the factors associated with clinical remission of MC.

Methods

This was a single‐center study of 72 consecutive patients who received treatment with IFN alfa‐2b (3 million IU 3 times a week; n = 32 patients) or PEGylated IFN alfa‐2b (PEG–IFN alfa‐2b) (1.5 μg/kg/week; n = 40 patients), both in combination with oral ribavirin (600–1,200 mg/day), for at least 6 months. Logistic regression was used to assess factors associated with clinical remission of MC.

Results

The mean ± SD duration of followup after discontinuation of antiviral therapy was 39.7 ± 24.4 months. Eight deaths (11.1% of patients) occurred during the study, primarily as a result of cardiovascular disease, liver disease, or infection. A complete clinical response of the MC occurred in 45 patients (62.5%), a sustained virologic response occurred in 58.3%, and cryoglobulins cleared in 45.8%. Compared with patients treated with IFN alfa‐2b plus ribavirin, those receiving PEG–IFN alfa‐2b plus ribavirin had a higher sustained clinical (67.5% versus 56.3%), virologic (62.5% versus 53.1%), and immunologic (57.5% versus 31.3%) response, regardless of HCV genotype and viral load. In multivariate analyses, an early virologic response (odds ratio 3.53 [95% confidence interval 1.18–10.59]) was independently associated with a complete clinical response of MC. A glomerular filtration rate ≤70 ml/minute (odds ratio 0.18 [95% confidence interval 0.05–0.67]) was negatively associated with a complete clinical response of MC.

Conclusion

PEG–IFN alfa‐2b plus ribavirin should be considered as induction therapy for HCV‐MC vasculitis. An early virologic response and the absence of renal insufficiency are the key factors in the clinical response.

     

Current therapy for hepatitis C

Introduction Pegylated interferon alfa in combination with ribavirin has been established as standard therapy for chronic hepatitis C virus (HCV) infection with sustained virologic response rates of 54–63%. The duration of therapy depends on the HCV genotype with currently 48 weeks for genotype 1 and 24 weeks for genotypes 2 and 3. Results and discussion The probability of sustained virologic response is very low (<1–2%) in genotype-1-infected patients without a 2-log decline of HCV RNA concentration after 12 weeks of therapy, and treatment can therefore be discontinued early. Conclusion Efficient treatment of the multiple side-effects of interferon-based antiviral therapy is essential in order to improve compliance, prevent dose reduction or early discontinuation and therefore enhance the probability of sustained response. Future developments of interferon-based therapy aim at the individualisation of the duration of therapy according to the kinetics of viral reduction. Furthermore, direct antiviral drugs, which are currently under investigation in phase I/II clinical trials, will fundamentally expand the treatment options of HCV infection in the next few years.     

Firstline treatment for hepatitis C: combination interferon/ribavirin versus interferon monotherapy

In the initial treatment of chronic hepatitis C, interferon‐alfa (IFN‐α) monotherapy for 24–48 weeks induces sustained response rates of only 10–20%. Combination therapy with IFN‐α plus ribavirin induces a sustained response in 40–50% of patients, and can be now recommended as the firstline therapy for chronic hepatitis C. Stopping therapy at week 12 because of persistent viraemia is unnecessary with the combination therapy because later clearance of HCV RNA can still occur with a sustained response. Patients with HCV genotype 1 should receive 48 weeks of combination therapy, in contrast to 24 weeks for patients with genotypes 2 or 3. For patients who cannot tolerate the side effects of ribavirin, such as anaemia, IFN‐α at 3 MU three times weekly for 48 weeks is preferred as the initial therapy. The long‐acting pegylated IFN can be expected to enhance the efficacy of combination therapy in the treatment of chronic hepatitis C and appears to be much more potent as monotherapy. Further studies are needed to improve the current ‘half‐full’ status of chronic hepatitis C treatment.     

PEGylated interferon alfa‐2b and ribavirin treatment in patients with hepatitis C virus–related systemic vasculitis

Objective

Type II mixed cryoglobulinemia (MC) is a systemic vasculitis usually associated with hepatitis C virus (HCV), which may involve the skin, kidneys, and nervous system. Molecular evidence of antigen‐driven B cell proliferation is definitively provided in HCV‐associated type II MC, and HCV appears to be the key trigger. The present trial was established to investigate the efficacy of therapy with PEGylated interferon alfa‐2b (PEG–IFN alfa‐2b) plus ribavirin in patients with HCV‐related MC vasculitis.

Methods

Nine consecutive patients with HCV‐related MC received PEG–IFN alfa‐2b (1.5 μg/kg/week) subcutaneously plus oral ribavirin (800–1,200 mg/day) for at least 6 months. The response to treatment was analyzed by comparing clinical, immunologic, and virologic parameters at the initial evaluation with those observed during followup.

Results

The mean ± SD duration of therapy with PEG–IFN alfa‐2b plus ribavirin was 13.5 ± 2.8 months. After a mean period of 18.6 months following discontinuation of treatment, all 9 patients are alive. Seven patients (78%) had a sustained virologic response and were complete clinical responders. Serum cryoglobulin disappeared in 5 of 9 patients (56%), and complement levels normalized in 80% of the patients. One patient had a partial virologic response with a complete clinical response. In another patient, a clinical relapse of MC vasculitis occurred in association with the reappearance of HCV RNA. Treatment was well tolerated, and no patient had side effects for which discontinuation of therapy was required.

Conclusion

Treatment with PEG–IFN alfa‐2b plus ribavirin can achieve a complete clinical response in most patients with HCV‐related MC vasculitis. Complete clinical response correlates with the eradication of HCV and requires a shorter treatment period than that previously reported for IFNα plus ribavirin.

     

Hepatitis C virus： Virology, diagnosis and management of antiviral therapy

Hepatitis C virus (HCV) infects approximately 170 million individuals worldwide. Prevention of HCV infection complications is based on antiviral therapy with the combination of pegylated interferon alfa and ribavirin. The use of serological and virological tests has become essential in the management of HCV infection in order to diagnose infection, guide treatment decisions and assess the virological response to antiviral therapy. Anti- HCV antibody testing and HCV RNA testing are used to diagnose acute and chronic hepatitis C. The HCV genotype should be systematically determined before treatment, as it determines the indication, the duration of treatment, the dose of ribavirin and the virological monitoring procedure. HCV RNA monitoring during therapy is used to tailor treatment duration in HCV genotype 1 infection, and molecular assays are used to assess the end-of-treatment and, most importantly the sustained virological response, i.e. the endpoint of therapy.     

Treatment for hepatitis C virus in human immunodeficiency virus-infected patients: clinical benefits and cost-effectiveness

BACKGROUND: Hepatitis C virus (HCV) is an important cause of liver disease in human immunodeficiency virus (HIV)-infected patients. OBJECTIVE: To assess the cost-effectiveness of alternative management strategies for chronic HCV in co-infected patients with moderate hepatitis. METHODS: A state-transition model was used to simulate a cohort of HIV-infected patients with a mean CD4 cell count of 350 cells/ micro L and moderate chronic hepatitis C stratified by genotype. Strategies included interferon alfa (48 weeks), pegylated interferon alfa (48 weeks), interferon alfa and ribavirin (24 and 48 weeks), pegylated interferon alfa and ribavirin (48 weeks), and no treatment. Outcomes included life expectancy, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. RESULTS: Treatment for moderate chronic HCV with combination therapy using an interferon-based regimen reduced the incidence of cirrhosis and provided gains in quality-adjusted life expectancy ranging from 6.2 to 13.9 months, depending on genotype. Regardless of genotype, the cost-effectiveness of interferon alfa and ribavirin for patients with moderate hepatitis was lower than $50 000 per QALY vs the next best strategy. With genotype 1, pegylated interferon alfa (vs interferon alfa) and ribavirin therapy provided an additional 1.6 quality-adjusted life-months for $40 000 per QALY. Because treatment is more effective with non-1 genotypes, pegylated interferon (vs interferon alfa) and ribavirin provided only 3 additional quality-adjusted life-months for $105 300 per QALY. For patients who were intolerant of ribavirin, monotherapy with pegylated interferon was always the most cost-effective option. CONCLUSIONS: Combination therapy for moderate hepatitis in coinfected patients will increase quality-adjusted life expectancy and have a cost-effectiveness ratio comparable to that of other well-accepted clinical interventions.     

Response-guided therapy for patients with hepatitis C virus genotype 6 infection: a pilot study

Summary. The optimal duration of treatment with pegylated interferon (PEG‐IFN) plus ribavirin (RBV) in patients with hepatitis C virus (HCV) genotype 6 is unknown. This study was aimed at determining treatment response on the basis of rapid virological response (RVR) of HCV genotype 6 in comparison with genotypes 1 and 3. Sixty‐six treatment naïve patients were treated with PEG‐IFN‐α2a (180 μg/week) plus weight‐based RBV (1000–1200 mg/day). Patients with genotype 1 n = 16) and genotype 3 (n = 16) were treated for a fixed duration of 48 and 24 weeks, respectively. Patients with genotype 6 (n = 34) who achieved RVR were treated for 24 weeks (response‐guided therapy) and the remaining patients were treated for 48 weeks (standard therapy). The mean baseline HCV RNA levels were not statistically different between groups (6.4 ± 0.8, 6.0 ± 1.0 and 6.5 ± 0.8 Log₁₀ IU/mL for genotypes 1, 3 and 6, respectively). Patients with genotypes 1, 3 and 6 achieved RVR in 43.8%, 87.5% and 73.5% of cases, respectively. One patient with genotype 1 and 3 with genotype 6 were considered nonresponders and discontinued therapy. Sustained virological response (SVR) was achieved in 62.5%, 81.3% and 76.5% of patients with genotypes 1, 3 and 6, respectively. The SVR rate in patients with genotype 6 who underwent response‐guided therapy was 88%. This pilot study suggested that the SVR rate of HCV genotype 6 was at an intermediate level between those of genotypes 3 and 1. Treatment with PEG‐IFN plus RBV for 24 weeks may be sufficient for patients with genotype 6 who achieve RVR. Prospective randomized trials are required to evaluate this response‐guided strategy in a larger number of patients with genotype 6.     

Antiviral effects of amantadine and iminosugar derivatives against hepatitis C virus

Current therapy of chronic hepatitis C is based on the combination of pegylated interferon-alpha and ribavirin. In spite of 50% sustained virological response, therapy is still limited by unsatisfying success rates with genotype 1 infections and adverse side effects. One attempt to increase success rates is triple combination therapy of interferon and ribavirin with amantadine, a drug assumed to interfere with HCV p7 ion channel function. However, results from clinical trials indicate limited efficacy and the antiviral activity is unclear. In contrast, NS3 protease inhibitors have shown potent antiviral effects in clinical trials but rapid selection for drug resistance may limit their benefit. Targeting cellular factors required for HCV is therefore an attractive alternative. In this study, employing a system for production of infectious HCV particles in cell culture, we determined the antiviral effects of amantadine and iminosugar derivatives; the second of which primarily target host cell glucosidases required for folding and maturation of HCV envelope glycoproteins. We found that across a spectrum of HCV isolates and genotypes, amantadine affected neither RNA replication nor the release or infectivity of HCV particles. In agreement, p7 ion channel activity was not affected by amantadine, demonstrating that amantadine is not an HCV-selective antiviral. In contrast, a dose-dependent reduction of virus titers was achieved with iminosugars. Furthermore, HCV was rapidly eliminated from cell culture upon passage in the presence of a long alkyl chain deoxynojirimycin (DNJ). CONCLUSION: Iminosugar derivatives are potential drugs for treatment of HCV infections.     

In vivo interferon system assessed by 2′‐5′ oligoadenylate synthetase activity in chronic hepatitis C virus patients treated with pegylated interferon and ribavirin

Aim: 2′,5′ oligoadenylate synthetase (2‐5AS), an enzyme induced by interferon, is an accurate indicator of the antiviral effect of interferon. We measured it during pegylated interferon based therapies in patients with chronic hepatitis C virus (HCV) in order to determine the dynamics of antiviral status in vivo and the relationship between the response to exogenous interferon and the outcome of therapy. Methods: A total of 160 patients with chronic HCV were treated with pegylated interferon alfa 2a or 2b or non‐pegylated interferon, with or without ribavirin. Serum 2‐5AS activity was measured by radioimmunoassay assay kits every 2 weeks. Results: In 60 patients treated with pegylated interferon alfa 2a or 2b, 2‐5AS levels increased to 7–40 times (average 235 pmol/dL) above the pretreatment levels (30 pmol/dL), which were significantly higher than the levels during non‐pegylated interferon therapy. Ribavirin did not enhance 2‐5AS levels. 2‐5AS levels between sustained virological response (SVR) and non‐SVR, including null responders to pegylated interferon plus ribavirin therapy were not significantly different. Conclusion: 2‐5AS levels were significantly higher in patients treated with pegylated interferon than in those treated with non‐pegylated interferon, suggesting that pegylated interferon is more potent at inducing interferon response genes resulting in an improved antiviral effect. Ribavirin did not appear to be related to interferon response gene induction.     

Association between HCV amino acid substitutions and outcome of peginterferon and ribavirin combination therapy in HCV genotype 1b and high viral load

Background and Aim: We prospectively compared the sensitivity to interferon (IFN) and the efficacy of antiviral combination therapy with peginterferon (PEG‐IFN) and ribavirin for chronic hepatitis C virus (HCV) genotype 1b infection according to the amino acid sequences of the HCV core, E1, and NS5A regions reported to be associated with the outcome of antiviral therapy. Methods: A total of 107 patients with HCV genotype 1b were investigated. All patients received combination therapy with PEG‐IFN alpha‐2b and ribavirin. Amino acids 70 and 91 (core), 139 (E1), and 2209–2248 (NS5A) of HCV were analyzed by direct nucleotide sequencing. Results: The reduction in HCV RNA concentration at 24 h after a single administration of conventional IFN‐alpha and after the start of combination therapy was significantly less marked, and rates of complete early virologic response, end‐of‐treatment response, and sustained virologic response (SVR) were significantly lower (all P < 0.0001) in patients with glutamine at amino acid 70 (n = 29) than in those with arginine at that position (n = 70). We found no differences associated with the other amino acid positions. Amino acid 70 was an independent factor for the responses to the therapy in multivariate analysis. Conclusion: The identity of amino acid 70 of the HCV core region affected the sensitivity to IFN; patients with glutamine at amino acid 70 of HCV showed resistance to IFN. Consequently, it strongly affected the outcome of combination therapy with PEG‐IFN and ribavirin in Japanese patients with HCV genotype 1b.     

Triple therapy with boceprevir or telaprevir for prior HCV non-responders

Approximately 170 million people are infected with hepatitis C virus (HCV) worldwide. Sustained virological response (SVR) is equivalent to viral eradication and associated with a reduction in the risk of cirrhosis and hepatocellular carcinoma. The treatment for genotype 1 HCV chronic infection is the addition of a protease inhibitor (telaprevir or boceprevir) to the pegylated-interferon (PEG-IFN) plus ribavirin (RBV) regimen. Treatment of genotype 1 naïve chronic hepatitis C with PEG-IFN and ribavirin (RBV) for 48 weeks results in SVR in approximately 40% of patients. Retreatment of previous relapsers to PEG-IFN/RBV therapy with triple therapy, a protease inhibitor (telaprevir or boceprevir), plus PEG-IFN and RBV results in SVR in more than 70% of cases. However, retreatment of previous non-responders to PEG-IFN/RBV therapy with these triple therapies, results in SVR in less than 30% of cases. The aim of this review is to summarize results obtained with Boceprevir or Telaprevir triple therapy for prior HCV experienced patients (non-responders and relapsers).     

CIHR Canadian HIV Trials Network Co-Infection and Concurrent Diseases Core: Updated Canadian guidelines for the treatment of hepatitis C infection in HIV-hepatitis C coinfected adults

BACKGROUND:Hepatitis C virus (HCV) coinfection occurs in 20% to 30% of Canadians living with HIV and is responsible for a heavy burden of morbidity and mortality. Management of HIV-HCV coinfection is more complex due to the accelerated progression of liver disease, the timing and nature of antiretroviral and HCV therapy, mental health and addictions management, socioeconomic obstacles and drug-drug interactions between new HCV direct-acting antiviral therapies and antiretroviral regimens.OBJECTIVE:To update national standards for the management of HCV-HIV coinfected adults in the Canadian context.METHODS:A standing working group with specific clinical expertise in HIV-HCV coinfection was convened by The Canadian Institute of Health Research HIV Trials Network to review recently published data regarding HCV antiviral treatments and to update the Canadian HIV-HCV coinfection guidelines.RESULTS:Recent data suggest that the gap in sustained virological response rates between HCV monoinfection and HIV-HCV coinfection has been eliminated with newer HCV antiviral regimens. All HIV-HCV coinfected individuals should be assessed for HCV therapy. First-line treatment for genotypes 1 through 6 includes pegylated interferon and weight-based ribavirin dosing plus the nucleotide sofosbuvir for 12 weeks. Sofosbuvir in combination with the protease inhibitor simeprevir is another first-line consideration for genotype 1 infection. Sofosbuvir with ribavirin for 12 weeks (genotype 2) and 24 weeks (genotype 3) is also recommended as first-line treatment.DISCUSSION:Recommendations may not supersede individual clinical judgement.     

Efficacy of triple therapy with thymalfasin,peginterferon α-2a,and ribavirin for the treatment of hispanic chronic HCV nonresponders: Original Article

Background/Aims: Thymalfasin has shown efficacy in the treatment of chronic HCV infection. The aim of this study was to evaluate the efficacy and tolerability of triple therapy with thymalfasin, peginterferon α-2a (PEG-IFN α-2a), and ribavirin in Hispanic patients with chronic viral hepatitis C who were nonresponders to prior treatment with interferon alfa (IFN-α)/ribavirin. Methods: In this open-label study, 40 subjects received thymalfasin (1.6 mg twice a week), PEG-IFN α-2a (180 μg once a week), and ribavirin (800-1,000 mg/ day) for 48 weeks. All patients had positive HCV RNA by PCR analysis, abnormal levels of ALT, compensated hepatic disease, and liver biopsy with chronic damage. Results: Viral response was observed in 52.5% patients at week 12 and 50% at week 24. Of the per protocol group, 52.6% showed an end-of-treatment response at week 48 and 21.1% achieved an SVR at week 72. Among genotype 1 patients, 23.5% achieved an SVR at week 72. A reduction of the dose of PEG IFN α-2a and ribavirin was required. Thymalfasin was well tolerated without dose reduction. Conclusion: Triple therapy with thymalfasin, PEG IFN α-2a, and ribavirin is an effective treatment option for difficult-to-treat HCV patients who are refractory to prior conventional treatment, with adequate tolerability.